Department of Clinical Pharmacy and Education, Graduate School of Pharmaceutical Science, Kyoto University, Kyoto, Japan; Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Kyoto, Japan.
Department of Clinical Pharmacy and Education, Graduate School of Pharmaceutical Science, Kyoto University, Kyoto, Japan; Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Kyoto, Japan; Department of Pharmacy, Kobe University Hospital, Kobe, Japan.
Biol Blood Marrow Transplant. 2018 Jul;24(7):1441-1448. doi: 10.1016/j.bbmt.2018.01.040. Epub 2018 Feb 7.
Mycophenolate mofetil (MMF) is a prodrug of mycophenolic acid (MPA) and is frequently used to prevent acute graft-versus-host disease (aGVHD) in patients receiving hematopoietic stem cell transplantation (HSCT). However, optimal doses of MMF and target MPA concentrations in HSCT patients have not been defined. In this study, relationships between pharmacokinetic or pharmacodynamic markers of MPA and successful aGVHD prevention and neutrophil engraftment were evaluated to inform individualized MPA treatments in HSCT patients. We recruited 35 patients undergoing cord blood transplantation (CBT) who were treated with MMF. Area under the concentration-time curves from 0 to 24 hours (AUC) for free MPA and MPA acyl glucuronide (AcMPAG) at 1 week after the start of MMF treatments were significantly higher in patients with gastrointestinal (GI) aGVHD at stage ≥I than those at stage 0. Patients with faster neutrophil engraftment had higher free MPA AUC at 1 week after the start of MMF treatments compared with those with slower neutrophil engraftment. Inosine-5'-monophosphate dehydrogenase activity in peripheral blood mononuclear cells and single nucleotide polymorphisms in genes that were previously associated with MPA pharmacokinetics and pharmacodynamics were not an independent predictor for the clinical outcomes. Receiver-operating characteristic model analyses showed that cutoff values of AUC for successful GI aGVHD prevention were .689 and 15.6 µg⋅hour⋅mL for free MPA and AcMPAG, respectively. In addition, the cut-off value of free MPA AUC for neutrophil engraftment by day 25 was .405 µg⋅hour⋅mL. In conclusion, free MPA AUC may be a better predictor of the prevention of GI aGVHD and neutrophil engraftment compared with that of total MPA in patients receiving CBT. Hence, monitoring of the free MPA AUC between .405 and .689 µg⋅hour⋅mL could be considered informative of individualized MPA treatments in CBT patients.
霉酚酸酯（MMF）是霉酚酸（MPA）的前体药物，常用于预防接受造血干细胞移植（HSCT）的患者发生急性移植物抗宿主病（aGVHD）。然而，HSCT 患者中 MMF 的最佳剂量和 MPA 的目标浓度尚未确定。在这项研究中，评估了 MPA 的药代动力学或药效动力学标志物与成功预防 aGVHD 和中性粒细胞植入的关系，以期为 HSCT 患者的个体化 MPA 治疗提供信息。我们招募了 35 名接受脐带血移植（CBT）的患者，他们接受 MMF 治疗。与 0 期相比，在 MMF 治疗开始后 1 周时，发生胃肠道（GI）aGVHD 分级≥1 期的患者的游离 MPA 和 MPA 酰基葡萄糖醛酸（AcMPAG）的 0 至 24 小时浓度-时间曲线下面积（AUC）显著更高。与中性粒细胞植入较慢的患者相比，中性粒细胞植入较快的患者在 MMF 治疗开始后 1 周时的游离 MPA AUC 更高。外周血单个核细胞中肌苷-5'-单磷酸脱氢酶活性和先前与 MPA 药代动力学和药效动力学相关的基因中的单核苷酸多态性不是临床结局的独立预测因子。受试者工作特征模型分析显示，游离 MPA 用于成功预防 GI aGVHD 的 AUC 截断值分别为.689 和 15.6µg⋅hour⋅mL ，用于 AcMPAG。此外，中性粒细胞植入第 25 天的游离 MPA AUC 截断值为.405µg⋅hour⋅mL。总之，与 CBT 患者的总 MPA 相比，游离 MPA AUC 可能是预测 GI aGVHD 预防和中性粒细胞植入的更好指标。因此，在.405 至.689µg⋅hour⋅mL 之间监测游离 MPA AUC 可能有助于为 CBT 患者提供个体化的 MPA 治疗信息。
